1.3.1.1 TEXT PROPOSED FOR THE SUMMARY OF PRODUCT CHARACTERISTICS SEVIKAR HCT 20 mg/5 mg/12.5 mg, 40 mg/5 mg/12.5 mg, 40 mg/10 mg/12.5 mg, 40 mg/5 mg/25 mg, 40 mg/10 mg/25 mg Attached please find: Final SmPC Day 210

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SUMMARY OF PRODUCT CHARACTERISTICS

1. NAME OF THE MEDICINAL PRODUCT

SEVIKAR HCT 20 mg/5 mg/12.5 mg film-coated tablets SEVIKAR HCT 40 mg/5 mg/12.5 mg film-coated tablets SEVIKAR HCT 40 mg/10 mg/12.5 mg film-coated tablets SEVIKAR HCT 40 mg/5 mg/25 mg film-coated tablets SEVIKAR HCT 40 mg/10 mg/25 mg film-coated tablets

2. QUALITATIVE AND QUANTITATIVE COMPOSITION

SEVIKAR HCT 20 mg/5 mg/12.5 mg film-coated tablets: Each film-coated tablet contains 20 mg olmesartan medoxomil, 5 mg amlodipine (as amlodipine besilate) and 12.5 mg hydrochlorothiazide. SEVIKAR HCT 40 mg/5 mg/12.5 mg film-coated tablets: Each film-coated tablet contains 40 mg olmesartan medoxomil, 5 mg amlodipine (as amlodipine besilate) and 12.5 mg hydrochlorothiazide. SEVIKAR HCT 40 mg/10 mg/12.5 mg film-coated tablets: Each film-coated tablet contains 40 mg olmesartan medoxomil, 10 mg amlodipine (as amlodipine besilate) and 12.5 mg hydrochlorothiazide. SEVIKAR HCT 40 mg/5 mg/25 mg film-coated tablets: Each film-coated tablet contains 40 mg olmesartan medoxomil, 5 mg amlodipine (as amlodipine besilate) and 25 mg hydrochlorothiazide. SEVIKAR HCT 40 mg/10 mg/25 mg film-coated tablets: Each film-coated tablet contains 40 mg olmesartan medoxomil, 10 mg amlodipine (as amlodipine besilate) and 25 mg hydrochlorothiazide. Excipients:

For a full list of excipients, see section 6.1. 3. PHARMACEUTICAL FORM

Film-coated tablet. SEVIKAR HCT 20 mg/5 mg/12.5 mg film-coated tablets: Light orange, round, film-coated tablet of 8 mm debossed C51on one side. SEVIKAR HCT 40 mg/5 mg/12.5 mg film-coated tablets: Light yellow, round, film-coated tablet of 9.5 mm debossed C53 on one side.

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SEVIKAR HCT 40 mg/10 mg/12.5 mg film-coated tablets: Greyish red, round, film-coated tablet of 9.5 mm debossed C55 on one side. SEVIKAR HCT 40 mg/5 mg/25 mg film-coated tablets: Light yellow, oval, film-coated tablet of 15 x 7 mm debossed C54 on one side. SEVIKAR HCT 40 mg/10 mg/25 mg film-coated tablets: Greyish red, oval, film-coated tablet of 15 x 7 mm debossed C57 on one side.

4. CLINICAL PARTICULARS 4.1 Therapeutic indications Treatment of essential hypertension.

SEVIKAR HCT is indicated as substitution therapy in adult patients whose blood pressure is adequately controlled on the combination of olmesartan medoxomil, amlodipine and hydrochlorothiazide, taken as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine).

4.2 Posology and method of administration Adults

The recommended dose of SEVIKAR HCT is 1 tablet per day. Patients should be controlled on stable doses of olmesartan medoxomil, amlodipine and hydrochlorothiazide taken at the same time as a dual-component (olmesartan medoxomil and amlodipine or olmesartan medoxomil and hydrochlorothiazide) and a single-component formulation (hydrochlorothiazide or amlodipine). The dose of SEVIKAR HCT has to be based on the doses of the individual components of the combination at the time of switching. The maximum recommended dose of SEVIKAR HCT is 40 mg/10 mg/25 mg per day. Method of administration: The tablet should be swallowed with a sufficient amount of fluid (e. g. one glass of water). The tablet should not be chewed and should be taken at the same time each day. SEVIKAR HCT can be taken with or without food. Elderly (age 65 years or over) Caution, including more frequent monitoring of blood pressure, is recommended in elderly patients, particularly at the maximum dose of SEVIKAR HCT 40 mg/10 mg/25 mg per day.

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Renal impairment

The maximum dose in patients with mild to moderate renal impairment (creatinine clearance of 30 – 60 mL/min) is SEVIKAR HCT 20 mg/5 mg/12.5 mg, owing to limited experience of the 40 mg olmesartan medoxomil dosage in this patient group. Monitoring of serum concentrations of potassium and creatinine is advised in patients with moderate renal impairment. The use of SEVIKAR HCT in patients with severe renal impairment (creatinine clearance < 30 mL/min) is contraindicated (see sections 4.3, 4.4 and 5.2).

Hepatic impairment

SEVIKAR HCT should be used with caution in patients with mild hepatic impairment (see sections 4.4 and 5.2). In patients with moderate hepatic impairment the maximum dose should not exceed SEVIKAR HCT 20 mg/5 mg/12.5 mg once daily. Close monitoring of blood pressure and renal function is advised in patients with hepatic impairment. SEVIKAR HCT should not be used in patients with severe hepatic impairment (see sections 4.3 and 5.2), cholestasis or biliary obstruction (see section 4.3). Paediatric population

SEVIKAR HCT is not recommended for use in patients aged below 18 years due to a lack of data on safety and efficacy.

4.3 Contraindications

Hypersensitivity to the active substances, to dihydropyridine derivates or to sulfonamide-derived substances (since hydrochlorothiazide is a sulfonamide-derived drug) or to any of the excipients (see section 6.1). Severe renal impairment (see sections 4.4 and 5.2). Refractory hypokalaemia, hypercalcaemia, hyponatraemia and symptomatic hyperuricaemia. Severe hepatic insufficiency, cholestasis and biliary obstructive disorders (see section 5.2). 2nd and 3rd trimester of pregnancy (see sections 4.4 and 4.6). Due to the amlodipine component, SEVIKAR HCT is contraindicated in patients with: - Shock (including cardiogenic shock). - Severe hypotension - Obstruction of the outflow tract of the left ventricle (e.g. high grade aortic stenosis). - Haemodynamically unstable heart failure after acute myocardial infarction.

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4.4 Special warnings and precautions for use Patients with hypovolaemia or sodium depletion: Symptomatic hypotension may occur in patients who are volume and/or sodium depleted as a result of diuretic therapy, dietary salt restriction, diarrhoea or vomiting, especially after the first dose. Correction of this condition prior to administration of SEVIKAR HCT or close medical supervision at the start of the treatment is recommended. Other conditions with stimulation of the renin-angiotensin-aldosterone system: In patients whose vascular tone and renal function depend predominantly on the activity of the renin-angiotensin-aldosterone system (e. g. patients with severe congestive heart failure or underlying renal disease, including renal artery stenosis), treatment with medicinal products that affect this system has been associated with acute hypotension, azotaemia, oliguria or, rarely, acute renal failure. Renovascular hypertension: There is an increased risk of severe hypotension and renal insufficiency when patients with bilateral renal artery stenosis or stenosis of the artery to a single functioning kidney are treated with medicinal products that affect the renin-angiotensin-aldosterone system. Renal impairment and kidney transplantation: When SEVIKAR HCT is used in patients with impaired renal function, periodic monitoring of serum concentrations of potassium and creatinine is recommended. Use of SEVIKAR HCT is not recommended in patients with severe renal impairment (creatinine clearance < 30 mL/min) (see sections 4.2, 4.3 and 5.2). Thiazide diuretic-associated azotaemia may occur in patients with impaired renal function. If progressive renal impairment becomes evident, careful reappraisal of therapy is necessary, with consideration given to discontinuing diuretic therapy. There is no experience of the administration of SEVIKAR HCT in patients with a recent kidney transplant or in patients with end-stage renal impairment (i. e. creatinine clearance < 12 mL/min). Hepatic impairment: Exposure to amlodipine and olmesartan medoxomil is increased in patients with hepatic impairment (see section 5.2). Furthermore, minor alterations of fluid and electrolyte balance during thiazide therapy may precipitate hepatic coma in patients with impaired hepatic function or progressive liver disease. Care should be taken when SEVIKAR HCT is administered in patients with mild to moderate hepatic impairment. In patients with moderate hepatic impairment, the dose of olmesartan medoxomil should not exceed 20 mg (see section 4.2). Use of SEVIKAR HCT is contraindicated in patients with severe hepatic impairment, cholestasis or biliary obstruction (see section 4.3). Aortic and mitral valve stenosis, obstructive hypertrophic cardiomyopathy: As with other vasodilators, special caution is indicated in patients suffering from aortic or mitral stenosis, or obstructive hypertrophic cardiomyopathy.

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Primary aldosteronism: Patients with primary aldosteronism generally will not respond to anti-hypertensive medicinal products acting through inhibition of the renin-angiotensin system. Therefore, the use of SEVIKAR HCT is not recommended in such patients. Metabolic and endocrine effects: Thiazide therapy may impair glucose tolerance. In diabetic patients dosage adjustments of insulin or oral hypoglycaemic agents may be required (see section 4.5). Latent diabetes mellitus may become manifest during thiazide therapy. Increases in cholesterol and triglyceride levels are undesirable effects known to be associated with thiazide diuretic therapy. Hyperuricaemia may occur or frank gout may be precipitated in some patients receiving thiazide therapy. Electrolyte imbalance: As for any patient receiving diuretic therapy, periodic determination of serum electrolytes should be performed at appropriate intervals. Thiazides, including hydrochlorothiazide, can cause fluid or electrolyte imbalance (including hypokalaemia, hyponatraemia and hypochloraemic alkalosis). Warning signs of fluid or electrolyte imbalance are dryness of the mouth, thirst, weakness, lethargy, drowsiness, restlessness, muscle pain or cramps, muscle fatigue, hypotension, oliguria, tachycardia, and gastrointestinal disturbances such as nausea or vomiting (see section 4.8). The risk of hypokalaemia is greatest in patients with cirrhosis of the liver, in patients experiencing brisk diuresis, in patients who are receiving inadequate oral intake of electrolytes and in patients receiving concomitant therapy with corticosteroids or ACTH (see section 4.5). Conversely, due to antagonism at the angiotensin-II receptors (AT1) through the olmesartan medoxomil component of SEVIKAR HCT hyperkalaemia may occur, especially in the presence of renal impairment and/or heart failure, and diabetes mellitus. Adequate monitoring of serum potassium in patients at risk is recommended. Potassium-sparing diuretics, potassium supplements or potassium-containing salt substitutes and other medicinal products that may increase serum potassium levels (e. g. heparin) should be co-administered cautiously with SEVIKAR HCT (see section 4.5). There is no evidence that olmesartan medoxomil would reduce or prevent diuretic-induced hyponatraemia. Chloride deficit is generally mild and usually does not require treatment. Thiazides may decrease urinary calcium excretion and cause an intermittent and slight elevation of serum calcium in the absence of known disorders of calcium metabolism. Hypercalcaemia may be evidence of hidden hyperparathyroidism. Thiazides should be discontinued before carrying out tests for parathyroid function. Thiazides have been shown to increase the urinary excretion of magnesium, which may result in hypomagnesaemia.

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Dilutional hyponatraemia may occur in oedematous patients in hot weather. Lithium: As with other angiotensin II receptor antagonists, the coadministration of SEVIKAR HCT and lithium is not recommended (see section 4.5). Heart failure: As a consequence of the inhibition of the renin-angiotensin-aldosterone system, changes in renal function may be anticipated in susceptible individuals. In patients with severe heart failure whose renal function may depend on the activity of the renin-angiotensin-aldosterone system, treatment with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor antagonists has been associated with oliguria and/or progressive azotaemia and (rarely) with acute renal failure and/or death. In a long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure of non-ischaemic aetiology, amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo (see section 5.1).

Pregnancy: Angiotensin II receptor antagonists should not be initiated during pregnancy. Unless continued angiotensin II receptor antagonists therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started (see sections 4.3 and 4.6). Paediatric population: SEVIKAR HCT is not indicated in children and adolescents under the age of 18 years. Photosensitivity: Cases of photosensitivity reactions have been reported with thiazide diuretics (see section 4.8). If photosensitivity reaction occurs during treatment with SEVIKAR HCT, it is recommended to stop the treatment. If re-administration of the diuretic is deemed necessary, it is recommended to protect the areas exposed to the sun or to artificial UVA. Other: As with any antihypertensive agent, excessive blood pressure reduction in patients with ischaemic heart disease or ischaemic cerebrovascular disease could result in a myocardial infarction or stroke. Hypersensitivity reactions to hydrochlorothiazide may occur in patients with or without a history of allergy or bronchial asthma, but are more likely in patients with such a history. Exacerbation or activation of systemic lupus erythematosus has been reported with the use of thiazide diuretics. As with all other angiotensin II receptor antagonists, the blood pressure lowering effect of olmesartan is somewhat less in black patients than in non-black patients, however, this effect was not seen in the clinical trial with SEVIKAR HCT.

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4.5 Interaction with other medicinal products and other forms of interaction Potential interactions related to the SEVIKAR HCT combination:

Concomitant use not recommended Lithium: Reversible increases in serum lithium concentrations and toxicity have been reported during concomitant administration of lithium with angiotensin converting enzyme inhibitors and, rarely, with angiotensin II receptor antagonists. In addition, renal clearance of lithium is reduced by thiazides and consequently the risk of lithium toxicity may be increased. Therefore use of SEVIKAR HCT and lithium in combination is not recommended (see section 4.4). If use of the combination proves necessary, careful monitoring of serum lithium levels is recommended. Concomitant use requiring caution Baclofen: Potentiation of antihypertensive effect may occur. Non-steroidal anti-inflammatory medicinal products: NSAIDs (i.e. acetylsalicylic acid (> 3 g/day), COX-2 inhibitors and non-selective NSAIDs) may reduce the antihypertensive effect of thiazide diuretics and angiotensin II receptor antagonists. In some patients with compromised renal function (e. g. dehydrated patients or elderly patients with compromised renal function) the co-administration of angiotensin II receptor antagonists and agents that inhibit cyclooxygenase may result in further deterioration of renal function, including possible acute renal failure, which is usually reversible. Therefore, the combination should be administered with caution, especially in the elderly. Patients should be adequately hydrated and consideration should be given to monitoring of renal function after initiation of concomitant therapy and periodically thereafter. Concomitant use to be taken into account

Amifostine: Potentiation of antihypertensive effect may occur. Other antihypertensive agents: The blood pressure lowering effect of SEVIKAR HCT can be increased by concomitant use of other antihypertensive medicinal products. Alcohol, barbiturates, narcotics or antidepressants: Potentiation of orthostatic hypotension may occur.

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Potential interactions related to olmesartan medoxomil: Concomitant use not recommended Medicinal products affecting potassium levels: Concomitant use of potassium-sparing diuretics, potassium supplements, salt substitutes containing potassium or other medicinal products (e. g. heparin, ACE inhibitors) may lead to increases in serum potassium (see section 4.4). If medicinal products that affect potassium are to be prescribed in combination with SEVIKAR HCT, monitoring of serum potassium is advised. Additional information After treatment with antacid (aluminium magnesium hydroxide), a modest reduction in bioavailability of olmesartan was observed. Olmesartan medoxomil had no significant effect on the pharmacokinetics or pharmacodynamics of warfarin or the pharmacokinetics of digoxin. Coadministration of olmesartan medoxomil with pravastatin had no clinically relevant effects on the pharmacokinetics of either component in healthy subjects. Olmesartan had no clinically relevant inhibitory effects on human cytochrome P450 enzymes 1A1/2, 2A6, 2C8/9, 2C19, 2D6, 2E1 and 3A4 in vitro, and had no or minimal inducing effects on rat cytochrome P450 activities. No clinically relevant interactions between olmesartan and medicinal products metabolised by the above cytochrome P450 enzymes are expected. Potential interactions related to amlodipine Concomitant use requiring caution Effects of other medicinal products on amlodipine

CYP3A4 inhibitors: With concomitant use with the CYP3A4 inhibitor erythromycin in young patients and diltiazem in elderly patients respectively the plasma concentration of amlodipine increased by 22% and 50% respectively. However, the clinical relevance of this finding is uncertain. It cannot be ruled out that strong inhibitors of CYP3A4 (i. e. ketoconazole, itraconazole, ritonavir) may increase the plasma concentrations of amlodipine to a greater extent than diltiazem. Amlodipine should be used with caution together with CYP3A4 inhibitors. However, no adverse events attributable to such interaction have been reported.

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CYP3A4 inducers: There is no data available regarding the effect of CYP3A4 inducers on amlodipine. The concomitant use of CYP3A4 inducers (i. e. rifampicin, hypericum perforatum) may give a lower plasma concentration of amlodipine. Amlodipine should be used with caution together with CYP3A4 inducers. In clinical interaction studies grapefruit juice, cimetidine, aluminium/ magnesium (antacid) and sildenafil did not affect the pharmacokinetics of amlodipine. Effects of amlodipine on other medicinal products

The blood pressure-lowering effect of amlodipine adds to the blood pressure-lowering effects of other antihypertensive agents. In clinical interaction studies, amlodipine did not affect the pharmacokinetics of atorvastatin, digoxin, ethanol (alcohol), warfarin or ciclosporin. There is no effect of amlodipine on laboratory parameters. Potential interactions related to hydrochlorothiazide: Concomitant use not recommended Medicinal products affecting potassium levels: The potassium-depleting effect of hydrochlorothiazide (see section 4.4) may be potentiated by the coadministration of other medicinal products associated with potassium loss and hypokalaemia (e. g. other kaliuretic diuretics, laxatives, corticosteroids, ACTH, amphotericin, carbenoxolone, penicillin G sodium or salicylic acid derivatives). Such concomitant use is therefore not recommended. Concomitant use requiring caution Calcium salts: Thiazide diuretics may increase serum calcium owing to decreased excretion. If calcium supplements must be prescribed, serum calcium should be monitored and calcium dosage adjusted accordingly. Cholestyramine and colestipol resins: Absorption of hydrochlorothiazide is impaired in the presence of anionic exchange resins. Digitalis glycosides: Thiazide-induced hypokalaemia or hypomagnesaemia may favour the onset of digitalis-induced cardiac arrhythmias.

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Medicinal products affected by serum potassium disturbances: Periodic monitoring of serum potassium and ECG is recommended when SEVIKAR HCT is administered with medicinal products affected by serum potassium disturbances (e. g. digitalis glycosides and antiarrhythmics) and with the following torsades de pointes (ventricular tachycardia)-inducing medicinal products (including some antiarrhythmics), hypokalaemia being a predisposing factor to torsades de pointes (ventricular tachycardia): - Class Ia antiarrythmics (e. g. quinidine, hydroquinidine, disopyramide). - Class III antiarrythmics (e. g. amiodarone, sotalol, dofetilide, ibutilide). - Some antipsychotics (e. g. thioridazine, chlorpromazine, levomepromazine,

trifluoperazine, cyamemazine, sulpiride, sultopride, amisulpride, tiapride, pimozide, haloperidol, droperidol).

- Others (e. g. bepridil, cisapride, diphemanil, erythromycin IV, halofantrin, mizolastin, pentamidine, sparfloxacin, terfenadine, vincamine IV).

Non-depolarizing skeletal muscle relaxants (e. g. tubocurarine): The effect of nondepolarizing skeletal muscle relaxants may be potentiated by hydrochlorothiazide. Anticholinergic agents (e. g. atropine, biperiden): Increase of the bioavailability of thiazide-type diuretics by decreasing gastrointestinal motility and stomach emptying rate. Antidiabetic medicinal products (oral agents and insulin): The treatment with a thiazide may influence the glucose tolerance. Dosage adjustment of the antidiabetic medicinal product may be required (see section 4.4). Metformin: Metformin should be used with caution because of the risk of lactic acidosis induced by possible functional renal failure linked to hydrochlorothiazide. Beta-blockers and diazoxide: The hyperglycaemic effect of beta-blockers and diazoxide may be enhanced by thiazides. Pressor amines (e. g. noradrenaline): The effect of pressor amines may be decreased. Medicinal products used in the treatment of gout (e. g. probenecid, sulfinpyrazone and allopurinol): Dosage adjustment of uricosuric medicinal products may be necessary since hydrochlorothiazide may raise the level of serum uric acid. Increase in dosage of probenecid or sulfinpyrazone may be necessary. Coadministration of a thiazide may increase the incidence of hypersensitivity reactions to allopurinol. Amantadine: Thiazides may increase the risk of adverse effects caused by amantadine. Cytotoxic agents (e. g. cyclophosphamide, methotrexate): Thiazides may reduce the renal excretion of cytotoxic medicinal products and potentiate their myelosuppressive effects.

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Salicylates: In case of high dosages of salicylates hydrochlorothiazide may enhance the toxic effect of the salicylates on the central nervous system. Methyldopa: There have been isolated reports of haemolytic anaemia occurring with concomitant use of hydrochlorothiazide and methyldopa. Ciclosporin: Concomitant treatment with ciclosporin may increase the risk of hyperuricaemia and gout-type complications. Tetracyclines: Concomitant administration of tetracyclines and thiazides increases the risk of tetracycline-induced increase in urea. This interaction is probably not applicable to doxycycline.

4.6 Pregnancy and lactation Pregnancy Given the effects of the individual components in this combination product on pregnancy, the use of SEVIKAR HCT is not recommended during the first trimester of pregnancy (see section 4.4). The use of SEVIKAR HCT is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4). Olmesartan medoxomil The use of angiotensin II receptor antagonists is not recommended during the first trimester of pregnancy (see section 4.4). The use of angiotensin II receptor antagonists is contra-indicated during the 2nd and 3rd trimester of pregnancy (see sections 4.3 and 4.4). Epidemiological evidence regarding the risk of teratogenicity following exposure to ACE inhibitors during the first trimester of pregnancy has not been conclusive; however a small increase in risk cannot be excluded. Whilst there is no controlled epidemiological data on the risk with angiotensin II receptor antagonists, similar risks may exist for this class of drugs. Unless continued angiotensin receptor blocker therapy is considered essential, patients planning pregnancy should be changed to alternative anti-hypertensive treatments, which have an established safety profile for use in pregnancy. When pregnancy is diagnosed, treatment with angiotensin II receptor antagonists should be stopped immediately, and, if appropriate, alternative therapy should be started. Exposure to angiotensin II receptor antagonists therapy during the 2nd and 3rd trimesters is known to induce human fetotoxicity (decreased renal function, oligohydramnios, skull ossification retardation) and neonatal toxicity (renal failure, hypotension, hyperkalaemia) (see also section 5.3). Should exposure to angiotensin II receptor antagonists have occurred from the 2nd trimester of pregnancy, ultrasound check of renal function and skull is recommended. Infants, whose mothers have taken angiotensin II receptor antagonists should be closely observed for hypotension (see also sections 4.3 and 4.4).

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Hydrochlorothiazide There is limited experience with hydrochlorothiazide during pregnancy, especially during the first trimester. Animal studies are insufficient. Hydrochlorothiazide crosses the placenta. Based on the pharmacological mechanism of action of hydrochlorothiazide its use during the 2nd and 3rd trimester may compromise foeto-placental perfusion and may cause foetal and neonatal effects like icterus, disturbance of electrolyte balance and thrombocytopenia. Hydrochlorothiazide should not be used for gestational oedema, gestational hypertension or pre-eclampsia due to the risk of decreased plasma volume and placental hypoperfusion, without a beneficial effect on the course of the disease. Hydrochlorothiazide should not be used for essential hypertension in pregnant women except in rare situations where no other treatment could be used. Amlodipine Data on a limited number of exposed pregnancies do not indicate that amlodipine or other calcium receptor antagonists have a harmful effect on the health of the fetus. However, there may be a risk of prolonged delivery. Lactation Because no information is available regarding the use of SEVIKAR HCT during breastfeeding, SEVIKAR HCT is not recommended and alternative treatments with better established safety profiles during breast-feeding are preferable, especially while nursing a newborn or preterm infant. Olmesartan is excreted into the milk of lactating rats. However, it is not known whether olmesartan passes into human milk. It is not known whether amlodipine is excreted in breast milk. Similar calcium channel blockers of the dihydropyridine type are excreted in breast milk. Hydrochlorothiazide is excreted into human milk.

4.7 Effects on ability to drive and use machines

No studies on the effects on the ability to drive and use machines have been performed. However, it should be borne in mind that dizziness, headache, nausea or fatigue may occasionally occur in patients taking antihypertensive therapy and that these symptoms may impair the ability to react.

4.8 Undesirable effects

The safety of SEVIKAR HCT was investigated in a double blind clinical trial in 574 patients and the open label long term extension phase in 2112 patients receiving olmesartan medoxomil in combination with amlodipine and hydrochlorothiazide (Table 1). The following terminologies have been used in order to classify the occurrence of undesirable effects: Very common (≥1/10) Common (≥1/100 to <1/10) Uncommon (≥1/1,000 to <1/100) Rare (≥1/10,000 to <1/1,000) Very rare (<1/10,000), not known (cannot be estimated from the available data)

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Table 1: SEVIKAR HCT System Organ Class Frequency Undesirable effects Infections and infestations Common Upper respiratory tract infection,

nasopharyngitis, urinary tract infection Metabolism and nutrition disorders

Uncommon Hyperkalaemia, hypokalaemia

Common Dizziness, headache Nervous system disorders Uncommon Postural dizziness, presyncope

Ear and labyrinth disorders

Uncommon Vertigo

Common Hypotension Vascular disorders Uncommon Flushing

Respiratory, thoracic and mediastinal disorders

Uncommon Cough

Common Nausea, diarrhoea, constipation Gastrointestinal disorders Uncommon Dry mouth Common Muscle spasm, joint swelling Musculoskeletal,

connective tissue and bone disorders

Uncommon Muscle weakness

Renal and urinary disorders

Common Pollakiuria

Reproductive system and breast disorders

Uncommon Erectile dysfunction

General disorders and administration site conditions

Common Peripheral oedema, fatigue

Common Blood creatinine increased, blood urea increased, blood uric acid increased

Investigations

Uncommon Blood potassium decreased, gamma glutamyl transferase increased, alanine aminotransferase increased, aspartate aminotransferase increased

Further evaluation of data from open label studies revealed no new adverse events not already covered in the safety data for the mono substances or the dual combinations. Additional information on the individual components: Adverse reactions previously reported with one of the individual components or with a dual fixed-dose combination consisting of either olmesartan medoxomil plus amlodipine or of olmesartan medoxomil plus hydrochlorothiazide may be potential adverse reactions with SEVIKAR HCT, even if not observed in clinical trials with this product:

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Olmesartan medoxomil (active ingredient of SEVIKAR HCT) Further adverse reactions reported in either clinical studies or from post marketing data with olmesartan medoxomil monotherapy in hypertension were as follows (Table 2):

Table 2: Olmesartan medoxomil System Organ Class Frequency Undesirable effects Blood and the lymphatic system disorders

Very Rare Thrombocytopenia

Infections and infestations Common Gastroenteritis Cardiac disorders Uncommon Angina pectoris Respiratory, thoracic and mediastinal disorders

Common Rhinitis, pharyngitis

Uncommon Dyspepsia Gastrointestinal disorders Very Rare Vomiting, abdominal pain Uncommon Rash Skin and subcutaneous

tissue disorders Very Rare Pruritus, exanthema, allergic dermatitis, urticaria, angioneurotic oedema, face oedema

Common Arthritis, back pain, skeletal pain Musculoskeletal, connective tissue and bone disorders

Very rare Myalgia

Common Haematuria

Renal and urinary disorders

Very rare Acute renal failure, renal insufficiency Common Influenza-like symptoms, chest pain,

pain General disorders and administration site conditions Very rare Malaise, lethargy Investigations Common Increased creatine kinase,

liver enzyme elevations Single cases of rhabdomyolysis have been reported in temporal association with the intake of angiotensin II receptor blockers. A causal relationship, however, has not been established.

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Amlodipine (active ingredient of SEVIKAR HCT)

Further adverse reactions reported with amlodipine monotherapy were as follows (Table 3): Table 3: Amlodipine System Organ Class Frequency Undesirable effects Blood and the lymphatic system disorders

Very Rare Leucopenia, thrombocytopenia

Immune system disorders Very Rare Allergic reactions Metabolism and nutrition disorders

Very Rare Hyperglycaemia

Uncommon Insomnia, mood changes (including anxiety), depression

Psychiatric disorders

Rare Confusion Common Somnolence Uncommon Tremor, dysgeusia, syncope,

hypoaesthesia, paraesthesia

Nervous system disorders

Very Rare Hypertonia, peripheral neuropathy

Eye disorders Uncommon Visual disturbance (including diplopia)

Ear and labyrinth disorders

Uncommon Tinnitus

Uncommon Palpitations Cardiac disorders

Very Rare Myocardial infarction, arrhythmia (including bradycardia, ventricular tachycardia and atrial fibrillation)

Vascular disorders Very Rare Vasculitis

Respiratory, thoracic and mediastinal disorders

Uncommon Dyspnoea, rhinitis

Common Abdominal pain Uncommon Vomiting, dyspepsia, altered

bowel habits (including diarrhoea and constipation)

Gastrointestinal disorders

Very Rare Pancreatitis, gastritis, gingival hyperplasia

Hepato-biliary disorders Very Rare Hepatitis, jaundice, hepatic enzymes increased*

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Uncommon Alopecia, purpura, skin

discolouration, hyperhydrosis, pruritus, rash, exanthema

Skin and subcutaneous tissue disorders

Very Rare Angioedema, erythema multiforme, urticaria, exfoliative dermatitis, Stevens-Johnson syndrome, Quincke oedema, Photosensitivity

Musculoskeletal, connective tissue and bone disorders

Uncommon Arthralgia, myalgia, back pain

Renal and urinary disorders

Uncommon Micturition disorder, nocturia

Reproductive system and breast disorders

Uncommon Gynaecomastia

Common Oedema General disorders and administration site conditions Uncommon Chest pain, asthenia, pain,

malaise Investigations Uncommon Weight increase, weight

decrease *mostly consistent with cholestasis

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Hydrochlorothiazide (active ingredient of SEVIKAR HCT) Hydrochlorothiazide may cause or exacerbate volume depletion, which may lead to electrolyte imbalance (see section 4.4). Further adverse reactions reported with hydrochlorothiazide monotherapy were as follows (Table 4):

Table 4: Hydrochlorothiazide System Organ Class Frequency Undesirable effects Infections and infestations

Rare Sialadenitis

Blood and the lymphatic system disorders

Rare Leucopenia, neutropenia/agranulo-cytosis, aplastic anaemia, haemolytic anaemia, bone marrow depression

Common Electrolyte imbalance (including hyponatraemia, hypomagnesaemia, hypochloraemia, and hypercalcaemia), hyperglycaemia, glycosuria

Metabolism and nutrition disorders

Uncommon Anorexia, hyperuricaemia Psychiatric disorders Rare Depression, restlessness, sleep

disturbances, apathy Common Light-headedness, confusional state Uncommon Loss of appetite, syncope

Nervous system disorders

Rare Hypoaesthesia, paraesthesia, convulsions

Eye disorders Rare Xanthopsia, transient blurred vision, lacrimation decreased

Cardiac disorders Rare Cardiac arrhythmias

Uncommon Orthostatic hypotension Vascular disorders

Rare Necrotising angiitis (vasculitis, cutaneous vasculitis), thrombosis, embolism

Respiratory, thoracic and mediastinal disorders

Rare Dyspnoea (including dyspnoea in interstitial pneumonia and pulmonary oedema)

Common Gastric irritation, meteorism Rare Pancreatitis

Gastrointestinal disorders

Very Rare Paralytic ileus Hepato-biliary disorders Rare Jaundice (intrahepatic cholestatic

icterus), acute cholecystitis

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Uncommon Rash, photosensitivity reactions Skin and subcutaneous

tissue disorders Rare Cutaneous lupus erythematosus-like reactions, reactivation of cutaneous lupus erythematosus, anaphylactic reactions, toxic epidermal necrolysis

Muskuloskeletal and connective tissue disorders

Rare Paresis

Renal and urinary disorders

Rare Renal dysfunction, interstitial nephritis

General disorders and administration site conditions

Rare Fever

Further adverse events reported in clinical trials or from post marketing experience with a fixed-dose combination of olmesartan medoxomil and amlodipine and not already reported for SEVIKAR HCT, olmesartan medoxomil monotherapy or amlodipine monotherapy (Table 5):

Table 5: Combination of olmesartan medoxomil and amlodipine System Organ Class Frequency Undesirable effects Immune system disorders

Rare Drug hypersensitivity

Gastrointestinal disorders

Uncommon Upper abdominal pain

Reproductive system and breast disorders

Uncommon Libido decreased

Common Pitting oedema General disorders and administration site conditions Uncommon Lethargy, asthenia

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Further adverse events reported in clinical trials or from post marketing experience with a fixed-dose combination of olmesartan medoxomil and hydrochlorothiazide and not already reported for SEVIKAR HCT, olmesartan medoxomil monotherapy or hydrochlorothiazide monotherapy (Table 6):

Table 6: Combination of olmesartan medoxomil and hydrochlorothiazide System Organ Class Frequency Undesirable effects Metabolism and nutrition disorders

Uncommon Hypertriglyceridaemia

Nervous system disorders

Not known Disturbances in consciousness (such as loss of consciousness)

Cardiac disorders Uncommon Palpitations

Skin and subcutaneous tissue disorders

Uncommon Eczema

Renal and urinary disorders

Not known Acute renal failure, abnormal renal function tests

Uncommon Blood potassium increased Investigations Rare Minor increases in blood urea

nitrogen values, minor decreases in mean haemoglobin and haematocrit values

4.9 Overdose Symptoms: The maximum dose of SEVIKAR HCT is 40 mg/10 mg/25 mg once daily. There is no information on overdosage with SEVIKAR HCT in humans. The most likely effect of SEVIKAR HCT overdosage is hypotension. The most likely effects of olmesartan medoxomil overdosage are hypotension and tachycardia; bradycardia could be encountered if parasympathetic (vagal) stimulation occurred. Amlodipine overdosage can be expected to lead to excessive peripheral vasodilatation with marked hypotension and possibly a reflex tachycardia. Marked and potentially prolonged systemic hypotension, up to and including shock with fatal outcome, has been reported. Overdosage with hydrochlorothiazide is associated with electrolyte depletion (hypokalaemia, hypochloraemia) and dehydration resulting from excessive diuresis. The most common signs and symptoms of overdose are nausea and somnolence. Hypokalaemia may result in muscle spasm and/or accentuate cardiac arrhythmias associated with the concomitant use of digitalis glycosides or certain anti-arrhythmic medicinal products.

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Treatment: In the event of overdosage with SEVIKAR HCT, treatment should be symptomatic and supportive. Management depends upon the time since ingestion and the severity of the symptoms. If intake is recent, gastric lavage may be considered. In healthy subjects, the administration of activated charcoal immediately or up to 2 hours after ingestion of amlodipine has been shown to reduce substantially the absorption of amlodipine. Clinically significant hypotension due to an overdose of SEVIKAR HCT requires active support of the cardiovascular system, including close monitoring of heart and lung function, elevation of the extremities, and attention to circulating fluid volume and urine output. A vasoconstrictor may be helpful in restoring vascular tone and blood pressure, provided that there is no contraindication to its use. Intravenous calcium gluconate may be beneficial in reversing the effects of calcium channel blockade. Serum electrolytes and creatinine should be monitored frequently. If hypotension occurs, the patient should be placed in a supine position, with salt and volume replacements given quickly. Since amlodipine is highly protein-bound, dialysis is not likely to be of benefit. The dialysability of olmesartan or hydrochlorothiazide is unknown. The degree to which olmesartan and hydrochlorothiazide are removed by haemodialysis has not been established.

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5. PHARMACOLOGICAL PROPERTIES 5.1 Pharmacodynamic properties

Pharmaco-therapeutic group: Angiotensin II antagonists, calcium channel blockers and diuretics. ATC code: C09DX03. SEVIKAR HCT is a combination of an angiotensin II receptor antagonist, olmesartan medoxomil, a calcium channel blocker, amlodipine besilate and a thiazide diuretic, hydrochlorothiazide. The combination of these ingredients has an additive antihypertensive effect, reducing blood pressure to a greater degree than each component alone. Olmesartan medoxomil is an orally active, selective angiotensin II receptor (type AT1) antagonist. Angiotensin II is the primary vasoactive hormone of the renin-angiotensin-aldosterone system and plays a significant role in the pathophysiology of hypertension. The effects of angiotensin II include vasoconstriction, stimulation of the synthesis and release of aldosterone, cardiac stimulation and renal reabsorption of sodium. Olmesartan blocks the vasoconstrictor and aldosterone-secreting effects of angiotensin II by blocking its binding to the AT1 receptor in tissues including vascular smooth muscle and the adrenal gland. The action of olmesartan is independent of the source or route of synthesis of angiotensin II. The selective antagonism of the angiotensin II (AT1) receptors by olmesartan results in increases in plasma renin levels and angiotensin I and II concentrations, and some decrease in plasma aldosterone concentrations. In hypertension, olmesartan medoxomil causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy. Once daily dosing with olmesartan medoxomil provides an effective and smooth reduction in blood pressure over the 24 hour dose interval. Once daily dosing produced similar decreases in blood pressure as twice daily dosing at the same total daily dose. With continuous treatment, maximum reductions in blood pressure are achieved by 8 weeks after the initiation of therapy, although a substantial proportion of the blood pressure lowering effect is already observed after 2 weeks of treatment. The effect of olmesartan medoxomil on mortality and morbidity is not yet known. The amlodipine component of SEVIKAR HCT is a calcium channel blocker that inhibits the transmembrane influx of calcium ions through the potential-dependent L-type channels into the heart and smooth muscle. Experimental data indicate that amlodipine binds to both dihydropyridine and non-dihydropyridine binding sites. Amlodipine is relatively vessel-selective, with a greater effect on vascular smooth muscle cells than on cardiac muscle cells. The antihypertensive effect of amlodipine derives from a direct relaxant effect on arterial smooth muscle, which leads to a lowering of peripheral resistance and hence of blood pressure.

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In hypertensive patients, amlodipine causes a dose-dependent, long-lasting reduction in arterial blood pressure. There has been no evidence of first-dose hypotension, of tachyphylaxis during long-term treatment, or of rebound hypertension after abrupt cessation of therapy.

Following administration of therapeutic doses to patients with hypertension, amlodipine produces an effective reduction in blood pressure in the supine, sitting and standing positions. Chronic use of amlodipine is not associated with significant changes in heart rate or plasma catecholamine levels. In hypertensive patients with normal renal function, therapeutic doses of amlodipine reduce renal vascular resistance and increase glomerular filtration rate and effective renal plasma flow, without changing filtration fraction or proteinuria. In haemodynamic studies in patients with heart failure and in clinical studies based on exercise tests in patients with NYHA class II-IV heart failure, amlodipine was found not to cause any clinical deterioration, as measured by exercise tolerance, left ventricular ejection fraction and clinical signs and symptoms. A placebo-controlled study (PRAISE) designed to evaluate patients with NYHA class III-IV heart failure receiving digitalis, diuretics and ACE inhibitors, has shown that amlodipine did not lead to an increase in the risk of mortality and morbidity in patients with heart failure. In a follow-up, long-term, placebo controlled study (PRAISE-2) of amlodipine in patients with NYHA III and IV heart failure without clinical symptoms or objective findings suggestive of underlying ischaemic disease, on stable doses of ACE inhibitors, digitalis, and diuretics, amlodipine had no effect on total or cardiovascular mortaility. In this same population amlodipine was associated with increased reports of pulmonary oedema despite no significant difference in the incidence of worsening heart failure as compared to placebo. Hydrochlorothiazide is a thiazide diuretic. The mechanism of the antihypertensive effect of thiazide diuretics is not fully known. Thiazides affect the renal tubular mechanisms of electrolyte reabsorption, directly increasing excretion of sodium and chloride in approximately equivalent amounts. The diuretic action of hydrochlorothiazide reduces plasma volume, increases plasma renin activity and increases aldosterone secretion, with consequent increases in urinary potassium and bicarbonate loss, and decreases in serum potassium. The renin-aldosterone link is mediated by angiotensin II and therefore coadministration of an angiotensin II receptor antagonist tends to reverse the potassium loss associated with thiazide diuretics. With hydrochlorothiazide, onset of diuresis occurs at about 2 hours and peak effect occurs at about 4 hours post-dose, whilst the action persists for approximately 6-12 hours. Epidemiological studies have shown that long-term treatment with hydrochlorothiazide monotherapy reduces the risk of cardiovascular mortality and morbidity.

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Results of Clinical Studies In a 12-week, double-blind, randomised, placebo-controlled 4-arm study in 2492 patients (67% Caucasian patients), treatment with SEVIKAR HCT 40 mg/10 mg/25 mg resulted in significantly greater reductions in diastolic and systolic blood pressures than treatment with either of the corresponding dual combinations, olmesartan medoxomil 40 mg plus amlodipine 10 mg, olmesartan medoxomil 40 mg plus hydrochlorothiazide 25 mg and amlodipine 10 mg plus hydrochlorothiazide 25 mg, respectively. The additional blood pressure lowering effect from SEVIKAR HCT 40 mg/10 mg/25 mg compared to the analogous dual combinations was between -3.8 and -6.7 mmHg for seated diastolic and between -7.1 and -9.6 mmHg for seated systolic blood pressure and occurred within the first 2 weeks.

The proportions of patients reaching blood pressure goal (< 140/90 mmHg for non-diabetic patients and < 130/80 mmHg for diabetic patients) at week 12 ranged from 34.9% to 46.6% for the dual combination treatment groups compared to 64.3% for SEVIKAR HCT 40 mg/10 mg/25 mg.

5.2 Pharmacokinetic properties Concomitant administration of olmesartan medoxomil, amlodipine and hydrochlorothiazide had no clinically-relevant effects on the pharmacokinetics of either component in healthy subjects. Following oral administration of SEVIKAR HCT in normal healthy adults, peak plasma concentrations of olmesartan, amlodipine and hydrochlorothiazide are reached in about 1.5 to 3 hours, 6 to 8 hours, and 1.5 to 2 hours, respectively. The rate and extent of absorption of olmesartan medoxomil, amlodipine and hydrochlorothiazide from SEVIKAR HCT are the same as when administered as a dual-fixed combination of olmesartan medoxomil and amlodipine together with a hydrochlorothiazide single-component tablet or when administered as a dual-fixed combination of olmesartan medoxomil and hydrochlorothiazide together with a amlodipine single-component tablet with the same dosages. Food does not affect the bioavailability of SEVIKAR HCT. Olmesartan medoxomil: Absorption and distribution: Olmesartan medoxomil is a prodrug. It is rapidly converted to the pharmacologically active metabolite, olmesartan, by esterases in the gut mucosa and in portal blood during absorption from the gastrointestinal tract. No intact olmesartan medoxomil or intact side chain medoxomil moiety have been detected in plasma or excreta. The mean absolute bioavailability of olmesartan from a tablet formulation was 25.6%. The mean peak plasma concentration (Cmax) of olmesartan is reached within about 2 hours after oral dosing with olmesartan medoxomil, and olmesartan plasma concentrations increase approximately linearly with increasing single oral doses up to about 80 mg. Food had minimal effect on the bioavailability of olmesartan and therefore olmesartan medoxomil may be administered with or without food.

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No clinically relevant gender-related differences in the pharmacokinetics of olmesartan have been observed. Olmesartan is highly bound to plasma protein (99.7%), but the potential for clinically significant protein binding displacement interactions between olmesartan and other highly bound co-administered active substances is low (as confirmed by the lack of a clinically significant interaction between olmesartan medoxomil and warfarin). The binding of olmesartan to blood cells is negligible. The mean volume of distribution after intravenous dosing is low (16 – 29 L). Metabolism and elimination: Total plasma clearance of olmesartan was typically 1.3 L/h (CV 19%) and was relatively slow compared to hepatic blood flow (ca 90 L/h). Following a single oral dose of 14C-labelled olmesartan medoxomil, 10 - 16% of the administered radioactivity was excreted in the urine (the vast majority within 24 hours of dose administration) and the remainder of the recovered radioactivity was excreted in the faeces. Based on the systemic availability of 25.6%, it can be calculated that absorbed olmesartan is cleared by both renal excretion (ca 40%) and hepato-biliary excretion (ca 60%). All recovered radioactivity was identified as olmesartan. No other significant metabolite was detected. Enterohepatic recycling of olmesartan is minimal. Since a large proportion of olmesartan is excreted via the biliary route, use in patients with biliary obstruction is contraindicated (see section 4.3). The terminal elimination half life of olmesartan varied between 10 and 15 hours after multiple oral dosing. Steady state was reached after 2-5 days of dosing and no further accumulation was evident after 14 days of repeated dosing. Renal clearance was approximately 0.5 – 0.7 L/h and was independent of dose. Amlodipine: Absorption and distribution: After oral administration of therapeutic doses, amlodipine is slowly absorbed from the gastrointestinal tract. The absorption of amlodipine is unaffected by the concomitant intake of food. The absolute bioavailability of the unchanged compound is estimated to be 64% – 80%. Peak plasma levels are reached 6 to 12 hours post-dose. The volume of distribution is about 20 L/kg. The pKa of amlodipine is 8.6. Plasma protein binding in vitro is approximately 98%. Metabolism and elimination: The plasma elimination half-life varies from 35 to 50 hours. Steady-state plasma levels are reached after 7 – 8 consecutive days. Amlodipine is extensively metabolised to inactive metabolites. About 60% of the administered dose is excreted in the urine, about 10% of which in the form of unchanged amlodipine. Hydrochlorothiazide: Absorption and distribution: Following oral administration of olmesartan medoxomil and hydrochlorothiazide in combination, the median time to peak concentrations of hydrochlorothiazide was 1.5 to 2 hours after dosing. Hydrochlorothiazide is 68% protein bound in the plasma and its apparent volume of distribution is 0.83 – 1.14 L/kg.

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Metabolism and elimination: Hydrochlorothiazide is not metabolised in man and is excreted almost entirely as unchanged active substance in urine. About 60% of the oral dose is eliminated as unchanged active substance within 48 hours. Renal clearance is about 250 – 300 mL/min. The terminal elimination half-life of hydrochlorothiazide is 10 – 15 hours. Pharmacokinetics in special populations Paediatric Population: The European Medicines Agency has waived the obligation to submit the results of studies with SEVIKAR HCT in all subsets of the paediatric population in essential hypertension. Elderly: In hypertensive patients, the olmesartan AUC at steady state was increased by ca 35% in elderly patients (65 – 75 years old) and by ca 44% in very elderly patients (≥ 75 years old) compared with the younger age group (see section 4.2). This may be at least in part related to a mean decrease in renal function in this group of patients. The recommended dosage regimen for elderly patients is, however, the same, although caution should be exercised when increasing the dosage. The time to reach peak plasma concentrations of amlodipine is similar in elderly and younger subjects. Amlodipine clearance tends to be decreased with resulting increases in AUC and elimination half life in elderly patients. Increases in AUC and elimination half life in patients with congestive heart failure were as expected for the patient age group in this study (see section 4.4). Limited data suggest that the systemic clearance of hydrochlorothiazide is reduced in both healthy and hypertensive elderly patients compared to young healthy volunteers. Renal impairment: In renally impaired patients, the olmesartan AUC at steady state increased by 62%, 82% and 179% in patients with mild, moderate and severe renal impairment, respectively, compared to healthy controls (see sections 4.2 and 4.4). The pharmacokinetics of olmesartan medoxomil in patients undergoing haemodialysis has not been studied. Amlodipine is extensively metabolised to inactive metabolites. Ten percent of the substance is excreted unchanged in the urine. Changes in amlodipine plasma concentration are not correlated with the degree of renal impairment. In these patients, amlodipine may be administered at the normal dosage. Amlodipine is not dialysable. The half-life of hydrochlorothiazide is prolonged in patients with impaired renal function. Hepatic impairment: After single oral administration, olmesartan AUC values are 6% and 65% higher in mildly and moderately hepatically impaired patients, respectively, than in their corresponding matched healthy controls. The unbound fraction of olmesartan at 2 hours post-dose in healthy subjects, in patients with mild hepatic impairment and in patients with moderate hepatic impairment is 0.26%, 0.34% and 0.41%, respectively.

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Following repeated dosing in patients with moderate hepatic impairment, olmesartan mean AUC is again about 65% higher than in matched healthy controls. Olmesartan mean Cmax values are similar in hepatically-impaired and healthy subjects. Olmesartan medoxomil has not been evaluated in patients with severe hepatic impairment (see sections 4.2 and 4.4). The clearance of amlodipine is decreased and the half-life is prolonged in patients with impaired hepatic function, resulting in an increase in AUC of about 40% – 60% (see sections 4.2 and 4.4). Hepatic impairment does not significantly influence the pharmacokinetics of hydrochlorothiazide.

5.3 Preclinical safety data Olmesartan medoxomil/ Amlodipine /Hydrochlorothiazide combination Repeated dose toxicity study in rats demonstrated that the combined administration of olmesartan medoxomil, amlodipine and hydrochlorothiazide neither augmented any of the previously reported and existing toxicities of the individual agents, nor induced any new toxicity, and no toxicologically synergistic effects were observed. No additional mutagenicity, carcinogenicity, and reproductive toxicity studies for SEVIKAR HCT have been conducted based on the well-understood safety profile of the individual active ingredients. Olmesartan medoxomil In chronic toxicity studies in rats and dogs, olmesartan medoxomil showed similar effects to other AT1 receptor antagonists and ACE inhibitors: raised blood urea (BUN) and creatinine; reduction in heart weight; reduction of red cell parameters (erythrocytes, haemoglobin, heamatocrit); histological indications of renal damage (regenerative lesions of the renal epithelium, thickening of the basal membrane, dilatation of the tubules). These adverse effects caused by the pharmacological action of olmesartan medoxomil have also occurred in preclinical trials on other AT1 receptor antagonists and ACE inhibitors and can be reduced by simultaneous oral administration of sodium chloride. Like other AT1 receptor antagonists olmesartan medoxomil was found to increase the incidence of chromosome breaks in cell cultures in vitro, but not in vivo. The overall data of a comprehensive genotoxicity testing programme suggest that olmesartan is very unlikely to exert genotoxic effects under conditions of clinical use. Olmesartan medoxomil was not carcinogenic in rats or transgenic mice. In reproductive studies in rats, olmesartan medoxomil did not affect fertility and there was no evidence of a teratogenic effect. In common with other angiotensin II antagonists, survival of offspring was reduced and pelvic dilatation of the kidney was seen after exposure of the dams in late pregnancy and lactation. In rabbits there was no indication of a fetotoxic effect.

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Amlodipine Preclinical data reveal no special hazard for humans based on conventional studies of safety pharmacology, repeated dose toxicity, genotoxicity and carcinogenic potential. In animal studies with respect to the reproduction in rats at high doses delayed parturition, difficult labour and impaired fetal and pup survival were seen. Hydrochlorothiazide Studies with hydrochlorothiazide have shown equivocal evidence for a genotoxic or carcinogenic effect in some experimental models. However, the extensive human experience with hydrochlorothiazide has failed to show an association between its use and an increase in neoplasma.

6. PHARMACEUTICAL PARTICULARS 6.1 List of excipients

Tablet core • Starch, pregelatinised maize • Silicified microcrystalline cellulose (microcrystalline cellulose and silica colloidal

anhydrous) • Croscarmellose sodium • Magnesium stearate Film coat • Polyvinyl alcohol • Macrogol 3350 • Talc • Titanium dioxide (E 171) • Iron (III) oxide yellow (E 172) • Iron (III) oxide red (E 172) (20/5/12.5, 40/10/12.5, 40/10/25 film coated tablets only) • Iron (II, III) oxide black (E 172) (20/5/12.5 film coated tablets only)

6.2 Incompatibilities

Not applicable.

6.3 Shelf life

3 years. 6.4 Special precautions for storage

This medicinal product does not require any special storage conditions.

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6.5 Nature and contents of container Laminated polyamide / aluminium / polyvinyl chloride / aluminium blister. Packs of 14, 28, 30, 56, 84, 90, 98, 10 x 28 and 10 x 30 film-coated tablets. Packs with perforated unit dose blisters of 10, 50 and 500 film-coated tablets. 30 cc HDPE-bottles with a polypropylene child-resistant closure lined with innerseal and a silica gel dessicant. Packs of 7 and 30 film-coated tablets. 60 cc HDPE-bottles with a polypropylene child-resistant closure lined with innerseal and a silica gel dessicant. Packs of 90 film-coated tablets. Not all pack sizes may be marketed.

6.6 Special precautions for disposal and other handling

No special requirements. 7. MARKETING AUTHORISATION HOLDER

[To be completed nationally]

8. MARKETING AUTHORISATION NUMBERS [To be completed nationally]

9. DATE OF FIRST AUTHORISATION/RENEWAL OF AUTHORISATION

10. DATE OF REVISION OF THE TEXT

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